Just the right bullets: using viruses to treat disease

Just the right bullets: using viruses to treat disease

Laurence O’Dwyer

Laurence O’Dwyer writes that while gene therapy has enormous promise, it also involves complicated ethical questions.

The concept of using gene therapy to treat diseases at their origin has long appealed to researchers and clinicians. With advances in the design of vectors that use viruses to inject genes into cells, gene therapy has the potential to treat a wide array of genetic disorders in the near future.

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<a href=”http://adserver.adtech.de/adlink|3.0|289|1413727|0|277|ADTECH;loc=300;key=key1+key2+key3+key4″ target=”_blank”><img src=”http://adserver.adtech.de/adserv|3.0|289|1413727|0|277|ADTECH;loc=300;key=key1+key2+key3+key4″ border=”0″ width=”2″ height=”2″></a> Since the publication of On the Origin of Species in 1859, evolution and its flower, genetics, have wrapped themselves tightly around our perception of ourselves. Our 20,000 genes describe every detail of the cellular metropolis of the body, and the more we know about our genes, the more we can influence the goings on of the city.

A digital code

To begin at the beginning, we should say that our genes are made up of DNA, which is a digital code consisting of four bases – adenine, thymine, cytosine and guanine. Reams of this double-helix twist and turn like the whorls of a telephone cord inside our chromosomes.

The information in the helix can be read in segments called codons, and a gene is a series of codons. It is the confluence of parental genes in the embryo that produces the unique flow of each individual.

A perfect stream of DNA would produce a perfect biology but so far this has never been recorded. Our genes are damaged everyday by environmental elements such as sunlight, alcohol and stress. If the damage is not too severe, this wear and tear can be repaired by the body’s internal machinery.

However, beyond our control are inherited cellular catastrophes such as cystic fibrosis and muscular dystrophy — so-called monogenic diseases — caused by malfunctions in individual genes.

Success and failure

Ways of treating monogenic diseases by adding new genetic material into cells first began to be outlined in the late 1970s and since that time ‘gene therapy’ has gone through various waves of success and failure. While early research focussed on monogenic diseases, recent advances are now opening up the potential of gene therapy for common multi-gene disorders such as high blood pressure and diabetes.
The most common approach to gene therapy is to deliver a desired gene into target cells using a vector that is derived from a virus. Over millennia, viruses have developed efficient ways of reproducing by introducing genetic material into a host and forcing host cells to make viral proteins.

This hijacking of the cell’s machinery can be put to good use if the pathogenic genes in the virus are deleted and replaced with a therapeutic gene. The designed vector can therefore use cellular machinery to produce copies of a gene that is lacking in a particular disease.

The process of engineering such a vector is complex and obviously researchers must go to great lengths to prove that the wild-type pathogenic genes of a virus are completely crippled before they can be used as vectors.

Once stripped of its pathogenic genes, the virus must also retain the genes that enable it to infiltrate cells.

HIV is a retrovirus that is frequently used in gene therapy, owing partly to the fact that it has been studied extensively. A retroviral vector will insert its genes into the host’s DNA which means that when a cell divides, its daughter cells will also contain the therapeutic gene.

This long-term integration of the gene reduces the need for repeat applications of the vector.


Retroviruses have been used with some success in the treatment of a rare lethal disease called X-linked severe combined immunodeficiency (X-SCID) where the immune system is seriously compromised. To treat the disease, a vector is first used to introduce functioning copies of a gene into cultured stem cells that have been extracted from the patient’s bone marrow.

Stem cells are then transplanted back into the patient where they can now express the missing gene that produces the T-cells that are lacking in X-SCID.

A serious problem for retroviral vectors is that the genes are inserted into random positions in the host genome. If the insertion disrupts an important gene, such as one controlling cell division, then cancer can be triggered.

Zinc finger nucleases

Recent research has been assessing ways to overcome this problem by designing vectors that insert their genes into specific sites on a chromosome, using what are called zinc finger nucleases.

Another common type of virus used in gene therapy is the adenovirus. A vector engineered from an adenovirus does not integrate its genes into the host genome, but leaves them free in the nucleus.

This overcomes the problem of random insertion into the genome, but the disadvantage of this vector is that therapeutic genes are not passed on to daughter cells after cell division.

Multiple applications of the vector may be needed because of the short-term expression of the therapeutic gene.

Recent clinical trials in China have used an adenoviral vector to treat head and neck cancers where the p53 gene is known to be mutated in 60% of patients.

The p53 gene is critical for activating apoptosis which is a form of programmed cell death, a critical process for combating tumours. After a p53-carrying vector was injected directly into tumours once a week for eight weeks, the Chinese trial recorded complete regression of primary tumours in 64% of patients.

The treatment has now been approved for general use in China, but many researchers in Europe and America believe that larger clinical trials should be completed before full approval is granted.

Cystic fibrosis

With the advantages and disadvantages of different viral vectors, scientists are also engineering hybrids that combine the strengths of different viruses. In the case of cystic fibrosis where the lungs are clogged with mucous, the epithelial cells of the airways have proved difficult to target with a single vector. However, a controversial study at the University of Philadelphia created a vector using the envelope proteins of the Ebola virus together with parts of the HIV virus to target cultured airway cells.
As the envelope protein of Ebola binds strongly to cell-surface molecules in the airway epithelium, the hybrid succeeded in entering cultured airway cells as well as tracheal cells of mice. But despite the findings, concerns about the desirability of creating such a vector have largely halted research. Less controversial, and relatively common in gene therapy trials, are hybrids that use a lentivirus coated with the envelope proteins from a vesicular stomatitis virus. This vector can target an almost universal set of cells.

Clearly gene therapy has enormous promise. But its promise also carries a weight of questions for the future — such as what constitutes a normal or an abnormal genome, what restrictions should be placed on research, and to what extent every single fly in the amber of our genes should be taken out with these very expensive tweezers. It would be interesting to know what Darwin would make of the new technology. He was after all, not just a scientist, but a thinker, aware of the influence of his discoveries on his contemporaries.

A student of theology at Oxford, he struggled with his own conclusions about the evolutionary chain that echoes all the way back to our beginnings. But while DNA provides us with a link to our past and our future, we are unlikely to discover his views because, as one Nobel laureate remarked, no language has yet been invented that is comprehensible to both the living and the dead.

  • Laurence O’Dwyer
    holds a PhD in Neuroscience.
  • The views expressed above are those solely of the author(s) and in no way may be deemed to reflect the views or policy of either MSD Science Centre or Merck Sharp & Dohme Ireland (Human Health) Limited.

link back url: http://www.imt.ie/clinical/infections-immunology/just-the-right-bullets-using-v.html


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